Project Summary/Abstract Oxygen is critical for all aspects of human physiology. Accordingly, oxygen deprivation can significantly impair or alter cellular functions, which can have devastating consequences to human health and viability. Physiological events that block circulation and prevent the delivery of oxygen, such as heart attack or stroke, cause lethal damage to affected tissues and comprise the leading cause of death and disability in Western countries. In other physiological contexts, hypoxia can stimulate the growth and metastasis of cancer, another human disease of considerable significance. For these reasons, there is substantial interest in developing strategies for alleviating the pathological consequences of hypoxia. The nematode C. elegans has proven to be a powerful model for investigating the mechanisms of hypoxic injury and for identifying potential strategies for intervention. Enlisting the genetic advantages of C. elegans enabled mutagenic and RNAi screens which together identified over 200 genes involved in hypoxic injury. This finding was enlightening because it revealed that although the primary effect of oxygen deprivation is a simple failure of oxidative phosphorylation, the ultimate repercussions of hypoxia are decided by a multitude of metabolic and cellular functions. By discovering a plethora of new mechanisms involved in hypoxic injury C. elegans has provided a significant contribution to the field. We believe C. elegans presents the most advantageous model for further investigation into these mechanisms. The C. elegans germline harbors a diverse array of cell types and physiological environments, therefore we reasoned that it might be a particularly useful context for understanding novel ways in which hypoxia may impact cellular function. Our preliminary studies have confirmed this, and established the potential of the germline to investigate three important aspects of hypoxic injury. Our first aim is designed to identify general and cell-specific mechanisms of hypoxic injury. The second aim is to characterize a novel mechanism for inducing resistance to hypoxic injury. And our third aim is to understand how hypoxia causes tumors to form in the C. elegans germline. The powerful experimental tools and interesting physiological properties of the germline offer unique advantages for achieving each of our objectives. We expect these studies to be of considerable biomedical significance, as we will establish the potential of general and cell-specific interventions, determine the potential for inducible mechanisms of hypoxia resistance, and elucidate fundamental conserved mechanisms of hypoxia induced cancer formation.